The molecular pathogenesis and management of bronchial carcinoids

INTRODUCTION: In terms of well-differentiated neuroendocrine tumors (NETs), the lung is the second most common site of occurrence, after the gastro-entero-pancreatic axis, and comprises ～ 25% of all NETs which may occur in various parts of the body. Pulmonary NETs are classified into four groups including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma and large cell neuroendocrine carcinomas. Among pulmonary NETs, typical and atypical carcinoid tumors of the lung are generally indolent, but do have a (albeit low) potential to metastasize. AREAS COVERED: The molecular biology and novel molecular pathways and drug targets in bronchial carcinoids are reviewed in this paper. A full data search is performed through PubMed over the years 2000 - 2010 with key words 'neuroendocrine tumors of the lung, bronchial carcinoid, lung carcinoid, foregut carcinoid, pulmonary carcinoid, pulmonary NETs, lung NETs, molecular biology, autoradiography, nuclear medicine, treatment'; all relevant publications are included, together with selected publications prior to that date. EXPERT OPINION: Although lying at the benign end of the spectrum of pulmonary NETs, bronchial carcinoids can metastasize, and the pathogenesis of these tumors is poorly understood. Several intracellular signaling pathways are under investigation to define new targets for the successful treatment of these tumors. In terms of treatment, further research should additionally focus on the already known but promising drug options.     

Diffractaic acid, a novel proapoptotic agent, induces with olive oil both apoptosis and antioxidative systems in Ti-implanted rabbits

Usnea longissima Ach., a lichen species, is a traditional herbal medicine with anti-detrimental effects. We evaluated the in vivo effects of a major constituent of U. longissima, diffractaic acid, and the main fatty component of the Mediterranean diet, olive oil, against apoptosis, including various caspase activations and oxidative injury in surrounding tissues after titanium implantation in rabbit femurs. Furthermore, we evaluated the underlying molecular mechanisms. In this study, this lichen metabolite and olive oil activated caspase-dependent cell death with apoptotic morphology, which is distinctly different from necrosis. Both orally and locally administered olive oil and diffractaic acid exerted pro-apoptotic induction in tissues surrounding the implants in titanium-implanted rabbits through the activation of initiator caspases (Cas-2, -8 and -9) and executioner caspase (Cas-3). In addition, they displayed strong myeloperoxidase and inducible nitric oxide synthase activities, providing an alleviating effect. Furthermore, administrations of diffractaic acid and olive oil attenuated the Ti-alloy implantation, and decreased superoxide dismutase activity and total glutathione level in peri-implant tissues. These results demonstrate that diffractaic acid and olive oil are involved in the induction of apoptotic cell death both through caspase-dependent cell death and as an antioxidant. Thus, the data suggest that both diffractaic acid and olive oil could be developed as effective proapoptotic agents in various disorders treatments.     

Classical and Follicular Variant Papillary Thyroid Carcinoma: Comparison of Clinical,Ultrasonographical, Cytological,and Histopathological Features in 444 Patients

Follicular variant papillary thyroid carcinoma (FVPTC) is the most common variant of papillary thyroid carcinoma (PTC) after classical PTC (CPTC). In this study, we aimed to compare functional status, ultrasonographical features, cytological results, and histopathological characteristics of patients with CPTC and FVPTC. Preoperative thyroid functions, thyroid autoantibodies, ultrasonographical features, cytology, and histopathology results of 354 (79.9%) CPTC and 90 (20.3%) FVPTC patients were reviewed retrospectively. Sex distribution, mean age, thyroid autoantibody positivity, and thyroid dysfunctions were similar in two groups. Among 320 patients with preoperative ultrasonography (US) findings, a hypoechoic halo was observed more frequently (p = 0.003), and marginal irregularity was observed less commonly (p = 0.024) in FVPTC lesions. In CPTC, rate of malignant cytology (p = 0.001), and in FVPTC, rate of suspicious cytology (p < 0.001) were significantly higher. Histopathologically, mean tumor diameter was markedly higher in FVPTC compared to CPTC (16.89 ± 13.86 vs 10.64 ± 9.70 mm, p < 0.001), while capsular invasion and extrathyroidal spread were significantly lower in patients with FVPTC (p = 0.018 and p = 0.039, respectively). FVPTC tend to have more benign features in US and less malignant results in cytology. Higher tumor size in FVPTC might be explained by the recognition of clinical importance of these lesions after reaching particular sizes due to benign US features.     

Imatinib-induced apoptosis: a possible link to topoisomerase enzyme inhibition

What is known and Objective: Imatinib is a specific BCR/ABL inhibitor, commonly used for the treatment of chronic myeloid leukaemia (CML), a hematological malignancy resulting from a chromosomal translocation that generates the BCR/ABL fusion protein. Recent studies showed that the imatinib has cytotoxic and apoptotic effects on many BCR/ABL‐negative cancers. Numerous compounds with cytotoxic potential exert their functions by interfering with the DNA topoisomerase. In this study, we examined the effects of imatinib on tumour cell‐killing in relation to DNA topoisomerase enzyme inhibition. Methods: We determined the cytotoxicity by cell proliferation assay (XTT; tetrazolium hydroxide), using the human K562 CML cells, and loss of mitochondrial membrane potential by monitoring the changes in caspase‐3 enzyme activity. Type I and II topoisomerase activities were measured by supercoiled plasmid relaxation and minicircle DNA decatenation assays respectively. Results and Discussion: Imatinib‐induced apoptosis and inhibited cell proliferation in a dose‐dependent manner. We also found that the imatinib was effective in both type I and type II topoisomerase reactions to a varying degree between 94% and 7% for the concentration range of 1 mm– 0·02 mm in a dose‐dependent manner. What is new and Conclusion: Our results suggest that the inhibition of topoisomerases may be a significant factor in imatinib‐induced apoptosis in CML.     

Comparison of p38MAPK (mitogene activated protein kinase), p65 NFkappaB (nuclear factor kappa b) and EMMPRIN (extracellular matrix metalloproteinase inducer) expressions with tumor grade and stage of superficial and invasive bladder tumors

To identify the molecular mechanisms of bladder cancer invasion pathophysiology. To assess EMMPRIN, p65NFkappaB and p38MAPK expressions which play a role in signal transmission system of muscle and non muscle invasive bladder tumors. Fifty-seven patients with non muscle invasive tumors (mean age 65.2 +/- 16.1) and 34 patients with muscle invasive tumors (mean age 62.2 +/- 20.7) were included in this study. Normal tissue from the same patients' bladders were used as control group. Patients had either TUR or radical cystectomy and paraffin sections were prepared for immunohistochemistry. Expression density was evaluated semiquantitively according to tumor grade and invasion depth. Results were compared with Mann Whitney U, Wilcoxon W, Chi Square and variation analysis tests. MAPK and EMMPRIN expression was increased according to tumor grade (p < 0.05). These expressions were also significantly higher in muscle invasive tumors than in non muscle invasive ones (p < 0.05). In normal tissue samples of both TUR and radical cystectomy materials, EMMPRIN, NFkappaB and MAPK expressions were lower than in tumor samples (p < 0.05). NFkappaB wasn't related to tumor grade/stage (p > 0.05). It can be stated that MAPK and EMMPRIN expression is related to the grade of bladder tumor and that NFkappaB positivity is not related to the grade/stage of the disease. In future positivity of lymph nodes and visceral metastasis and survival must be assessed to define the relationship with the expressions in long term follow up studies involving a larger number of patients.     

Pituitary macroadenoma with persisting dense lymphocytic infiltration in a young male patient

Context: Lymphocytic anterior hypophysitis in association with a pituitary adenoma was reported previously. In rare instance, inflammatory infiltration was confined to adenoma tissue itself, excluding anterior pituitary. Case: The patient - a 27-year-old male - presented with visual field defect. Further examination revealed a pituitary mass with suprasellar extension. Hormonal evaluation indicated mild hyperprolactinemia (42 ng/ml, normal < 19). After transsphenoidal resection, a pituitary adenoma showing cytoplasmic immunoreactivity to prolactin was identified. Dense and diffuse lymphocytic infiltration was seen within the tumor. At 15th month, a second transsphenoidal operation was necessary because of rapid development of visual compromise and headache. Excised surgical specimen consistent with previously resected adenoma showed diffuse lymphocytic infiltration composed of B and T cells within the adenoma tissue again. Conclusion: Presence of dense, hypophysitis-like lymphocytic infiltration within pituitary adenoma tissue obtained by two consecutive operations may reflect an host-mediated immune reaction to tumor. This rare finding could be challenging in terms of differential diagnosis and follow-up course.     

Factors related to post-treatment chronic pain in breast cancer survivors: the interference of pain with life functions

The frequency and the intensity of chronic pain, as well as the related factors, were assessed in a cohort of breast cancer patients. The life functions were also questioned in patients who have post-treatment chronic pain. The scope of this retrospective study was a cohort of surgically-treated breast cancer patients with unilateral early stage disease who were under regular follow-up. Patients were eligible if they completed their treatments at least 6 months before and were free of disease. Patients who had a previous history of chronic pain syndrome, chronic debilitating disease, psychiatric diagnosis, and other cancers were excluded. All data regarding their demographics and treatments were recorded. Chronic pain was defined as the pain at treatment-related regions for a duration of at least three months after completion of treatment. Turkish version of "Brief Pain Inventory (Short Form)" was given to the patients with chronic pain in order to assess their pain intensity and life functions. The factors related to chronic pain were compared between patients with and without chronic pain. Eighty-five eligible female patients were included in the study. Thirty-nine (46%) patients declared that they had chronic pain. The mean VAS scale score was 4.1 +/- 2.4 cm in these patients. The mean age of patients with chronic pain (54.3 +/- 12.6 years) was significantly less than that of the ones without pain (60.4 +/- 13.6 years; p = 0.035). Radiotherapy was found to be significantly related to chronic pain (p=0.049; OR: 2.60; 95% CI 1.07-6.30). The VAS scores were 1.5 +/- 2.7 cm, 1.9 +/- 3.2 cm, 1.3 +/- 2.7 cm, 0.9 +/- 2.5 cm for general activity, mood, relations with other people, and sleep, respectively. Although almost half of the early stage breast cancer patients experienced post-treatment chronic pain, they rated the intensity of their pain as mild to moderate. Younger age and receiving radiotherapy were found to be significant contributing factors. The interference of post-treatment chronic pain with life functions was small. Overall, mood was found to be the most affected life function among all.